P300/CBP Regulates HIF-1 Dependent Sympathetic Activation and Hypertension by Intermittent Hypoxia.

Obstructive sleep apnea (OSA), a widespread breathing disorder, leads to intermittent hypoxia (IH). OSA patients and IH-treated rodents exhibit heightened sympathetic nerve activity and hypertension. Previous studies reported transcriptional activation of NADPH oxidases (Nox) by hypoxia-inducible factor-1 (HIF-1) contribute to autonomic dysfunction in IH treated rodents. Lysine acetylation, regulated by lysine acetyltransferase (KATs) and lysine deacetylase (KDACs), activates gene transcription and play an important role in several physiological and pathological processes. Present study tested the hypothesis that acetylation of HIF-1α, by p300/CBP (KAT) activates Nox transcription leading to sympathetic activation and hypertension. Experiments were performed on pheochromocytoma (PC)-12 cells and rats treated with IH. IH increased KAT activity, p300/CBP protein, HIF-1α lysine acetylation, HIF-1 transcription and HIF-1 binding to the Nox4 gene promoter in PC12 cells, and these responses were blocked by CTK7A, a selective p300/CBP inhibitor. Plasma norepinephrine (index of sympathetic activation) and blood pressures were elevated in IH treated rats. These responses were associated with elevated p300/CBP protein, HIF-1α stabilization, transcriptional activation of Nox2 and Nox4 genes and reactive oxygen species (ROS), and all these responses were absent in CTK7A treated IH rats. These findings suggest lysine acetylation of HIF-1α by p300/CBP is an important contributor to sympathetic excitation and hypertension by IH.